Field of the Invention
The present invention provides methods for generating anti-idiotypic antibodies and compositions comprising the antibodies.
Background Art
Anti-idiotypic antibodies are defined as antibodies that target specific epitopes, called isotopes, on another antibody that are unique for that target antibody. The collection of isotopes for a given antibody defines its idiotype, and is generally found in the complementarity determining regions (CDRs) of the targeted antibody. Polyclonal anti-idiotypic antibodies have been used experimentally since the 1950's, but it was not until the mid-1970's that a modern theory was proposed for how self-generated anti-idiotypic antibodies might help control the immune system by regulating antibody production (Jerne, 1974). The discovery of a method for producing monoclonal antibodies a year later (Köhler and Milstein, 1975) opened the door for the creation and isolation of monoclonal anti-idiotypic antibodies that have specificity for a unique variable domain found exclusively on a specific target antibody. In support of the idiotype-anti-idiotype immune regulation theory, dosing neonatal mice with anti-idiotypic antibodies derived from perinatal B cell fusions was shown to greatly alter the B cell repertoire by possibly limiting the expression or expansion of self-reactive B cells (Kearney et al., 1989).
The utility of monoclonal anti-idiotypic antibodies has been demonstrated in a number of ways. To date, the most common usage of anti-idiotype monoclonal antibodies has been the in vitro development of pharmacokinetic enzyme-linked immunosorbant assays (ELISAs) that measure circulating sera levels of a dosed monoclonal antibody, or simply as a positive standard for measurement of anti-idiotype immune responses to therapeutic mouse (HAMA), chimeric (HACA), or human (HAHA) monoclonal antibodies (Liu et al., 2003). The specificity of an anti-idiotypic antibody allows for the detection of only the antibody of interest in the presence of endogenous polyclonal circulating antibody. Accurate quantification of circulating therapeutic antibody levels is an important and frequently challenging aspect of antibody drug development.
Another use of anti-idiotypic antibodies is the exploitation of their variable domain as a physical “internal image” of the anti-idiotype's target idiotope. The creation of a second generation anti-idiotype antibody to the first anti-idiotype antibody has the potential to target idiotopes that mimic epitopes found on the original antigen (Rodríquez et al., 2003). This can allow for the creation of new antibodies to the original antigen with subtly different binding characteristics to the same or proximal epitopes.
Along this same theme, anti-idiotypic monoclonal antibodies can be used as vaccines, especially to non-protein or potentially toxic pathogens. This has been demonstrated in vivo by immunizing mice with an anti-idiotype monoclonal to an anti-lipopolysaccharide (LPS) antibody, thereby generating circulating antibody that can bind the original LPS antigen and provide protection to the mice during a subsequent and otherwise lethal LPS challenge (Field et al., 1994). Another enterprising use of anti-idiotypic monoclonal antibodies is as a potential therapy for B cell lymphomas (Levy and Miller, 1990). Since generating anti-idiotypic antibodies has been difficult and time consuming, these efforts were not focused on providing individualized therapies, but rather by generating cross-reactive anti-idiotypic antibodies that recognized shared idiotopes of the B-cell receptors on clonally distinct lymphomas from multiple patients. Interest in this form of anti-lymphoma therapy peaked in the early 1990's and was eventually eclipsed by the success of the pan-B cell-selective anti-CD20 therapy, rituximab (Czuczman et al., 1999).
The generation of anti-idiotype serum titers in mice for monoclonal antibody generation can be challenging and requires prolonged immunizations. Immunizations of non-mouse species such as rats or hamsters with mouse antibodies frequently generate non-anti-idiotypic antibodies due to the antigenic dominance exhibited by Heavy (H) and Light (L) chain constant (C) region epitopes and result in antibodies to isotypes that may or may not be strain or even species specific. Syngeneic immunizations of mice using antibody-carrier conjugates to keyhole limpet hemocyanin (KLH) (Raychaudhuri et al., 1986) or antibody in less-favored CFA emulsions (Yakulis et al., 1972) have been successful in generating anti-idiotypic antibodies, but both approaches require multiple immunizations over the course of months.